Composition, in particular cosmetic, containing 7-hydroxy dhea and/or 7-keto dhea and at least an isoflavonoid

ABSTRACT

The invention concerns a composition containing, in a physiologically acceptable medium: (a) at least a DHEA derivative selected among 7-hydroxy DHEA and 7-keto DHEA, and (b) at least an isoflavonoid. The invention also concerns cosmetic and dermatological uses of said composition, in particular for preventing or treating actinic skin ageing symptoms.

[0001] The present invention relates to a composition containing7-hydroxy-DHEA and/or 7-keto-DHEA and at least one isoflavonoid, and tothe use of said composition, in particular for preventing or treatingthe signs of actinic skin aging.

[0002] DHEA, or dehydroepiandrosterone, is a natural steroid which ismainly produced by the corticoadrenal glands. Exogenous DHEA,administered topically or orally, is known for its capacity to promotekeratinization of the epidermis (JP-07 196 467) and to treat dry skinsby increasing the endogenous production and the secretion of sebum andby thus reinforcing the barrier effect of the skin (U.S. Pat. No.4,496,556). There has also been described in patent U.S. Pat. No.5,843,932 the use of DHEA for treating atrophy of the dermis byinhibiting the loss of collagen and of connective tissue. Finally, theapplicant has demonstrated the capacity of DHEA to control the weatheredappearance of the skin (FR 00/00349), and to modulate the pigmentationof the skin and of the hair (FR 99/12773) and to control atrophy of theepidermis (FR 00/06154). These properties of DHEA make it a candidate ofchoice as anti-aging active agent.

[0003] Among the metabolites of DHEA, particular attention has been madein the last few years to 7α-hydroxy-DHEA. It has indeed beendemonstrated that this metabolite, which does not possess the hormonalactivity of DHEA, made it possible to increase the proliferation of thefibroblasts and the viability of the human keratinocytes and hadanti-free radical effects (WO 98/40074). It has also been demonstrated,on rats (WO 00/28996), that 7α-hydroxy-DHEA increased the thickness ofthe dermis and the elastin and collagen content of the skin. It has thusbeen suggested to use this metabolite of DHEA for preventing and/ortreating the harmful effects of UV radiation on the skin, forcontrolling wrinkles and for increasing skin firmness and tone.

[0004] 7α-Hydroxy-DHEA is, with 5-androstene-3β,17β-diol, a majormetabolite of DHEA, which is obtained by the action of 7α-hydroxylase onDHEA. Among the minor metabolites of DHEA, there may be mentioned7β-hydroxy-DHEA, which is obtained by the action of 7β-hydroxylase onDHEA and 7-keto-DHEA, which is itself a metabolite of 7β-hydroxy-DHEA.

[0005] In the remainder of this description, the expression“7-hydroxy-DHEA” will be used to designate without distinction7α-hydroxy-DHEA and 7β-hydroxy-DHEA.

[0006] It is now evident to the applicant that the combination of7-hydroxy-DHEA and/or 7-keto-DHEA with an isoflavonoid could make itpossible to more effectively prevent or treat the signs of skin aging,in particular of actinic aging or photoaging.

[0007] The subject of the present invention is therefore a compositioncontaining, in a physiologically acceptable medium: (a) at least oneDHEA derivative chosen from 7-hydroxy-DHEA and 7-keto-DHEA, and (b) atleast one isoflavonoid.

[0008] 7-Hydroxy-DHEA is preferably 7α-OH-DHEA. A method for preparingthis compound is described in particular in Patent Applications FR-2 771105 and WO 94/08588. However, 7β-OH-DHEA is also suitable for use in thepresent invention.

[0009] The concentration of DHEA derivative in the composition accordingto the invention is advantageously between 0.0000001% and 10% by weight,preferably between 0.00001% and 5% by weight, relative to the totalweight of the composition.

[0010] The composition according to the present invention contains, incombination with the DHEA derivative, at least one isoflavonoid.

[0011] Isoflavonoids constitute a subclass of flavonoids, consisting ofa 3-phenylchroman backbone which may contain various substituents anddifferent levels of oxidation. Unlike flavonoids, they are only presentin a very limited number of plants.

[0012] The term isoflavonoid covers several classes of compounds amongwhich there may be mentioned isoflavones, isoflavanones, rotenoids,pterocarpans, isoflavans, isoflavan-3-enes, 3-arylcoumarins,3-aryl-4-hydroxycoumarins, coumestans, coumaronochromones or2-arylbenzofurans. In this regard, reference may be advantageously made,for a complete review of isoflavonoids, their methods of analysis andtheir sources, to chapter 5 “Isoflavonoids”, written by P. M. Dewick, inThe Flavonoids, publisher Harbone, pp. 125-157 (1988).

[0013] The isoflavonoids which are suitable for use in the presentinvention may be of natural or synthetic origin. The expression “naturalorigin” is understood to mean the isoflavonoid, in the pure state or insolution at various concentrations, obtained by various methods ofextraction from a component, generally a plant, of natural origin. Theexpression “synthetic origin” is understood to mean the isoflavonoid, inthe pure state or in solution at various concentrations, obtained bychemical synthesis.

[0014] It is preferable to use isoflavonoids of natural origin. Amongthese, there may be mentioned: daidzin, genistin, daidzein,formononetin, cuneatin, genistein, isoprunetin and prunetin, cajanin,orobol, pratensein, santal, junipegenin A, glycitein, afrormosin,retusin, tectorigenin, irisolidone, jamaicin, and their analogs andmetabolites.

[0015] The isoflavonoid preferably represents from 10⁻¹⁰% to 10%, andpreferably from 10⁻⁸ to 5%, of the total weight of the composition. Ofcourse, if the isoflavonoid is present in the form of a solutioncontaining a plant extract, persons skilled in the art will know how toadjust the quantity of this solution in the composition according to theinvention so as to obtain the above isoflavonoid concentration ranges.

[0016] The isoflavones are preferred for use in the present invention.This term is understood to mean both the aglycone forms (daidzein,genistein, glycitein) and the glycosylated forms (daidzin, genistin,glycitin) of the isoflavones.

[0017] Methods for preparing isoflavones are described in particular inWO 95/10530, WO 95/10512, U.S. Pat. No. 5,679,806, U.S. Pat. No.5,554,519, EP-812 837 and WO 97/26269.

[0018] However, for use in the present invention, it is preferable touse the isoflavones in the form of soybean extracts marketed by ICHIMARUPHARCOS under the trade name Flavosterone SB® and by ARCHER DANIELSMIDLAND COMPANY under the trade name Novasoy®. These extractspredominantly contain isoflavones in glycosylated form, which can bemetabolized in the body to their aglycone forms, and aglyconeisoflavones as minor components.

[0019] Isoflavones are in particular known as antioxidants, for theiranti-free radical and depigmenting properties, and for inhibiting theactivity of the sebaceous glands (see in particular DE-44 32 947). Theyhave also been described as agents for preventing the signs of skinaging, including flabby skin and the loss of radiance of the complexion(JP 1-96106).

[0020] It will therefore be appreciated that the combination of a DHEAderivative as defined above with isoflavonoids makes it possible toreinforce the anti-aging effects of the composition containing them, inparticular when this involves preventing or treating the signs ofactinic skin aging.

[0021] The composition according to the invention is preferably suitablefor topical application to the skin. It may be provided in all thegalenic forms normally used for this type of application, in particularin the form of an aqueous or oily solution, an oil-in-water orwater-in-oil or multiple emulsion, a silicone emulsion, a microemulsionor nanoemulsion, an aqueous or oily gel or a liquid, pasty or solidanhydrous product.

[0022] This composition may be fluid to a greater or lesser degree andmay have the appearance of a white or colored cream, an ointment, amilk, a lotion, a serum, a paste, a mousse or a gel. It may beoptionally applied to the skin in aerosol form. It may also be providedin solid form, for example in the form of a stick. It may be used as acare product and/or as a make-up product for the skin.

[0023] In a known manner, the composition of the invention may alsocontain the customary adjuvants in the cosmetic and dermatologicalfields, such as hydrophilic or lipophilic gelling agents, hydrophilic orlipophilic active agents, preservatives, antioxidants, solvents,perfumes, fillers, screening agents, pigments, odor absorbers andcoloring matter. The quantities of these various adjuvants are thoseconventionally used in the fields considered, and are for example from0.01 to 20% of the total weight of the composition. These adjuvants,depending on their nature, can be introduced into the fatty phase orinto the aqueous phase. These adjuvants, and their concentrations,should be such that they do not adversely affect the advantageousproperties of the DHEA derivatives, or of the isoflavonoids according tothe invention.

[0024] When the composition according to the invention is an emulsion,the proportion of the fatty phase may range from 5 to 80% by weight, andpreferably from 5 to 50% by weight relative to the total weight of thecomposition. The fatty substances, the emulsifiers and the coemulsifiersused in the composition in the form of an emulsion are chosen from thoseconventionally used in the field considered. The emulsifier and thecoemulsifier are preferably present in the composition in a proportionranging from 0.3 to 30% by weight, and preferably from 0.5 to 20% byweight relative to the total weight of the composition.

[0025] As fatty substances which can be used in the invention, it ispossible to use oils and in particular mineral oils (liquid paraffin),oils of plant origin (avocado oil, soybean oil), oils of animal origin(lanolin), synthetic oils (perhydrosqualene), silicone oils(cyclomethicone) and fluorinated oils (perfluoropolyethers). It is alsopossible to use, as fatty substances, fatty alcohols such as cetylalcohol, fatty acids, waxes and gums, and in particular silicone gums.

[0026] As emulsifiers and coemulsifiers which can be used in theinvention, there may be mentioned, for example, esters of fatty acidsand of polyethylene glycol such as PEG-100 stearate, PEG-50 stearate andPEG-40 stearate; esters of fatty acids and of polyols such as glycerylstearate, sorbitan tristearate, oxyethylenated sorbitan stearates whichare available under the trade names Tween® 20 or Tween® 60, for example;and mixtures thereof.

[0027] As hydrophilic gelling agents, there may be mentioned inparticular carboxyvinyl polymers (carbomer), acrylic copolymers such asacrylate/alkyl acrylate copolymers, polyacrylamides, polysaccharides,natural gums and clays, and, as lipophilic gelling agents, there may bementioned modified clays such as bentones, metal salts of fatty acidsand hydrophobic silica.

[0028] According to one variant of the invention, the composition may besuitable for administration by the oral route. In this case, it may beprovided in the form of syrups, suspensions, solutions, emulsions,granules, capsules or tablets, for example.

[0029] The daily doses of DHEA derivative which are administered by theoral route may be between 1 and 100 mg/day, preferably between 25 and 75mg/day. Preferably, the DHEA derivative is present in the compositionaccording to the invention in a quantity allowing its administration ata dose between 50 and 100 mg/day, said dosage being obtained in one ormore doses, with a unit dose of 50 mg.

[0030] The daily doses of isoflavonoids administered by the oral routeshould be defined on a case by case basis, in order to obtain thedesired physiological effect. More particularly, in the case ofisoflavones, alone or in an extract, the daily isoflavone doses may bebetween 0.1 and 500 mg/day. Preferably, the isoflavones are present inthe composition according to the invention in a quantity allowing itsadministration at a dose between 10 and 300 mg/day. Said dosage beingobtained in one or more doses.

[0031] In all cases, the composition according to the invention and/orthe preparation obtained therefrom comprises an effective quantity ofDHEA derivative and an effective quantity of isoflavonoid, sufficient toobtain the desired effect, in a physiologically acceptable medium.

[0032] The composition according to the invention finds application inparticular in the prevention and treatment of the signs of skin aging,in particular of actinic aging.

[0033] The present invention therefore also relates to the cosmetic useof the abovementioned composition for the prevention or treatment of thesigns of skin aging, in particular of actinic aging.

[0034] It relates in particular to the cosmetic use of the compositiondescribed above for preventing or controlling the formation of wrinklesand/or for improving skin tone and/or for increasing skin firmness.

[0035] The present invention also relates to the cosmetic use of thecomposition described above for preventing or controlling the harmfuleffects of UV radiation on the skin.

[0036] It finally relates to the use of the composition described abovefor manufacturing a preparation intended for preventing or controllingthe harmful effects of UV radiation on the skin.

[0037] The invention will now be illustrated by the followingnonlimiting examples. In these examples, the quantities are indicated asa percentage by weight.

EXAMPLE 1 Composition Topical Application

[0038] Phase A1 2-Octyldodecanol   20% 7α-OH-DHEA   1% Phase A2Polyglyceryl distearate (2 mol)   2% PEG monostearate (8 EO) 1.35%Stearic acid   1% Preservative  0.1% Phase B Preservatives 0.35%Neutralizing agents 0.25% Propylene glycol   5% Soybean aqueous extractcontaining 0.2% of   5% isoflavones and 30% of butylene glycol(Flavosterone SB - ICHIMARU PHARCOS) Water qs  100% Phase C Gellingagent  0.5% Neutralizing agent  0.2% Water qs

[0039] This composition may be prepared in the following manner: phasesA1, A2 and B are prepared separately by mixing their constituents in thehot state, with stirring. Phases A1 and A2 are mixed in the hot state,and then phase B is added to them. After cooling to room temperature,phase C is added to the mixture thus obtained.

[0040] This composition may be used as twice-daily applications forpreventing or treating the signs of skin aging such as wrinkles andflabby skin.

Example 2 Composition for Oral Administration

[0041] Soft gelatin capsules having the following composition areprepared in a manner which is conventional for persons skilled in theart: Hydrogenated soybean oil 40 mg Wheat oil 95 mg Soybean lecithin 20mg Natural tocopherols  5 mg Soybean extract available under the nameNovasoy ® 120 mg  from AMD (corresponding to approximately 50 mg ofisoflavones) 7α-OH-DHEA 50 mg

1. A composition containing, in a physiologically acceptable medium: (a)at least one DHEA derivative chosen from 7-hydroxy-DHEA and 7-keto-DHEA,and (b) at least one isoflavonoid.
 2. The composition as claimed inclaim 1, characterized in that the 7-hydroxy-DHEA is 7α-OH-DHEA.
 3. Thecomposition as claimed in claim 1, characterized in that the7-hydroxy-DHEA is 7β-OH-DHEA.
 4. The composition as claimed in any oneof claims 1 to 3, characterized in that said isoflavonoid is chosen fromisoflavonoids of natural origin.
 5. The composition as claimed in claim4, characterized in that said isoflavonoid is chosen from isoflavones.6. The composition as claimed in claim 4 or 5, characterized in thatsaid isoflavonoid is chosen from daidzin, genistin, daidzein,formononetin, cuneatin, genistein, isoprunetin and prunetin, cajanin,orobol, pratensein, santal, junipegenin A, glycitein, afrormosin,retusin, tectorigenin, irisolidone, jamaicin, and their analogs andmetabolites.
 7. The composition as claimed in claim 6, characterized inthat said isoflavonoid is chosen from daidzein, genistein, glycitein,daidzin, genistin and glycitin.
 8. The composition as claimed in any oneof claims 1 to 7, characterized in that it is suitable for topicalapplication to the skin.
 9. The composition as claimed in claim 8,characterized in that it contains from 0.0000001 to 10% by weight ofDHEA derivative, relative to the total weight of the composition. 10.The composition as claimed in claim 9, characterized in that it containsfrom 0.00001 to 5% by weight of DHEA derivative, relative to the totalweight of the composition.
 11. The composition as claimed in any one ofclaims 8 to 10, characterized in that it comprises from 10⁻¹⁰% to 10% byweight of isoflavonoid, relative to the total weight of the composition.12. Composition as claimed in claim 11, characterized in that itcomprises from 10⁻⁸% to 5% by weight of isoflavonoid, relative to thetotal weight of the composition.
 13. The composition as claimed in anyone of claims 1 to 7, characterized in that it is suitable foradministration by the oral route.
 14. The cosmetic use of thecomposition as claimed in any one of claims 1 to 13 for the preventionor treatment of the signs of skin aging, in particular of actinic aging.15. The cosmetic use of the composition as claimed in any one of claims1 to 13 for preventing or controlling the formation of wrinkles and/orfor improving skin tone and/or for increasing skin firmness.
 16. Thecosmetic use of the composition as claimed in any one of claims 1 to 13for preventing or controlling the harmful effects of UV radiation on theskin.
 17. The use of the composition as claimed in any one of claims 1to 13 for the manufacture of a composition intended for preventing orcontrolling the harmful effects of UV radiation on the skin.